Role of E3 ubiquitin ligases in insulin resistance

Yang, Xuan; Li, Yong-Jiang; Yang, Yi

doi:10.1111/dom.12677

Cited by 28 publications

(24 citation statements)

References 97 publications

(168 reference statements)

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“…E3 ubiquitin ligases have been implicated in the pathogenesis of insulin resistance by modulating insulin signaling (see review [42]). Much of the data underlying this model comes from targeted analysis of ubiquitination of individual insulin signaling intermediates [43, 44], rather than the systematic analysis of global changes in ubiquitome in pre-clinical models of insulin resistance presented here.…”

Section: Resultsmentioning

confidence: 99%

Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver

et al. 2017

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Ubiquitin is a crucial post-translational modification regulating numerous cellular processes, but its role in metabolic disease is not well characterized. In this study, we identified the in vivo ubiquitin-modified proteome in rat liver and determined changes in this ubiquitome under acute insulin stimulation and high-fat and sucrose diet-induced insulin resistance. We identified 1267 ubiquitinated proteins in rat liver across diet and insulin-stimulated conditions, with 882 proteins common to all conditions. KEGG pathway analysis of these proteins identified enrichment of metabolic pathways, TCA cycle, glycolysis/gluconeogenesis, fatty acid metabolism, and carbon metabolism, with similar pathways altered by diet and insulin resistance. Thus, the rat liver ubiquitome is sensitive to diet and insulin stimulation and this is perturbed in insulin resistance.

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Section: Resultsmentioning

confidence: 99%

Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver

et al. 2017

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“…How protein ubiquitination regulates metabolic events is far less understood. Emerging evidence suggests that E3 ligases could be important regulators of glucose metabolism (47). For example, the ubiquitin E3 ligase MG53 promotes IRS-1 ubiquitination and degradation and therefore contributes to obesity and metabolic syndrome upon chronic HFD (48,49).…”

Section: Discussionmentioning

confidence: 99%

DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver

et al. 2017

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Targeted protein degradation through ubiquitination is an important step in the regulation of glucose metabolism. Here, we present evidence that the DDB1-CUL4A ubiquitin E3 ligase functions as a novel metabolic regulator that promotes FOXO1-driven hepatic gluconeogenesis. In vivo, hepatocyte-specific Ddb1 deletion leads to impaired hepatic gluconeogenesis in the mouse liver but protects mice from high-fat diet–induced hyperglycemia. Lack of Ddb1 downregulates FOXO1 protein expression and impairs FOXO1-driven gluconeogenic response. Mechanistically, we discovered that DDB1 enhances FOXO1 protein stability via degrading the circadian protein cryptochrome 1 (CRY1), a known target of DDB1 E3 ligase. In the Cry1 depletion condition, insulin fails to reduce the nuclear FOXO1 abundance and suppress gluconeogenic gene expression. Chronic depletion of Cry1 in the mouse liver not only increases FOXO1 protein but also enhances hepatic gluconeogenesis. Thus, we have identified the DDB1-mediated CRY1 degradation as an important target of insulin action on glucose homeostasis.

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“…Hippo was GSM391694 GSM391695 GSM391696 GSM391697 GSM391693 GSM391705 GSM391706 GSM391698 GSM391709 GSM391699 GSM391707 GSM391708 GSM391703 GSM391704 GSM391710 GSM391700 GSM391702 reported as a modulator of metabolism in the liver, disruption of the Hippo pathway might be associated with development of type 2 diabetes 35 . Hypoxia-inducible factor-1 signaling pathway contributed to insulin resistance 36,37 , and might be involved in hepatic insulin sensitivity in HepG2 cells 38 . Activation of the PI3K-Akt pathway would attenuate hepatic insulin resistance 39,40 , and reduce gluconeogenesis in type 2 diabetes mice 41 .…”

Section: Discussionmentioning

confidence: 99%

Key genes and co‐expression network analysis in the livers of type 2 diabetes patients

Pan

Yang

2019

J of Diabetes Invest

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Aims/Introduction The incidence of type 2 diabetes is increasing worldwide. Hepatic insulin resistance and liver lipid accumulation contributes to type 2 diabetes development. The aim of the present study was to investigate the key gene pathways and co‐expression networks in the livers of type 2 diabetes patients. Materials and Methods Dataset GSE 15653 containing nine healthy individuals and nine type 2 diabetes patients was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. Differentially expressed genes were obtained from the livers of type 2 diabetes patients, annotated pathway enrichment and protein–protein interaction network analysis. Next, functional modules and transcription factor networks were constructed. Gene co‐expression networks were analyzed by weighted correlation network analysis to identify key modules related to clinical traits, and the candidate key genes were validated in hepatic insulin resistance models in vitro . Results A total of 778 differentially expressed genes were filtered in the livers of type 2 diabetes patients, pathway enrichment analysis identified ke y pathways, such as the mitogen‐activated protein kinase signaling pathway, Hippo signaling pathway and hypoxia‐inducible factor ‐1 signaling pathway, that were associated with type 2 diabetes. Several transcription factors of three functional modules identified from protein–protein interaction networks are likely to be implicated in type 2 diabetes. Furthermore, weighted correlation network analysis identified five modules that were shown to be highly correlated with type 2 diabetes and other clinical traits. Functional annotation showed that these modules were mainly enriched in pathways such as metabolic pathways, phosphoinositide 3‐kinase‐protein kinase B signaling pathway and natural killer cell‐mediated cytotoxicity. UBE 2M and GPER were upregulated in L02 and HepG2 models, whereas P2 RY 11 only upregulated in L02 model, and UBE 2N only downregulated in HepG2 model at a significant level. Conclusions These results would offer new insights into hepatic insulin resistance, type 2 diabetes pathogenesis, development and drug discovery.

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Role of E3 ubiquitin ligases in insulin resistance

Cited by 28 publications

References 97 publications

Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver

Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver

DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver

Key genes and co‐expression network analysis in the livers of type 2 diabetes patients

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